2-(5&#39;-nitro-2&#39;-furyl)-4-amino-thieno(3,2-d) pyrimidines and salts thereof

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(5-(O2-N-)FUR-2-YL),4-R2,6-R1-THIENO(3,2-D)PYRIMIDINE   WHEREIN R1 IS HYDROGEN OR METHYL, AND R2 IS AMINO, (ALKYL OR 1 TO 5 CARBON ATOMS)-AMINO, DI(ALKYL OF 1 TO 4 CARBON ATOMS)-AMINO, (MONOHYDROXYALKYL OF 2 TO 5 CARBON ATOMS)-AMINO, (2,3-DIHYDROXY-NPROPYL)-AMINO, (ALKOXY OF 1 TO 2 CARBONATOMS-ALKYL OF 1 TO 3 CARBON ATOMS)-AMINO, N-(W-HYDROXY-ALKYL OF 2 TO 3 CARBON ATOMS)-N(ALKYL OF 1 TO 4 CARBON ATOMS)AMINO, NARBON ATOMS)-N(ALKYL OF 1 TO 4 CARBON ATOMS)AMINO, N-METHYL-D-GLUCAMINO, DI-(HYDROXY-ALKYL OF 1 TO 5 CARBON ATOMS)-AMINO, ((DI-ALKYL OF 1 TO 2 CARBON ATOMS)-AMINO-ALKYL OF 2 TO 3 CARBON ATOMS)-AMINO, (1METHYL-2-HYDROXY-ETHYL)-AMINO, (2-PHENYL-2-HYDROXYETHYL)-AMINO, (2-HYDROXY-3-DIETHYLAMINO-N-PROPYL)AMINO- (ALKANOL OF 1 TO 2 CARBON ATOMS)-AMINO, CHLOROACETYL-AMINO, DICHLOROACETYL - AMINO, (AMINOALKYL OF 2 TO 3 CARBON ATOMS)-AMINO, (ACETYL-AMINOALKYL OF 2 TO 3 CARBON ATOMS)-AMINO, ALKYLAMINO, ANILINO, CHLOROANILIANO, METHYLANILINO, HYDROXYANILINO, METHOXYANILINO, N-METHYL-ANILINO, BENZYLAMINO, PHENETHYL-AMINO, CYCLOHEXYL-AMINO, (HYDROXY-CYCLOHEXYL)AMINO, PYRROLIDINO, PIPERIDINO, HYDROXY-PIPERIDINO, MORPHOLINO, THIOMORPHOLINO, THIOMORPHOLINO-1-OXIDE, PIPERAZINO, N-METHYL-PIPERAZINO, N-HYDROXYETHYLPIPERAZINO, N-FORMYL-PIPERAZINE OR N-CARBETHOXYPIPERAZINO, AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABEL ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS BACTERICIDAL AGENTS AGAINST GRAMPOSITIVE AND GRAMNEGATIVE BACTERIA, AS FUNGICIDES AND AS THRICHOMONACIDES, ESPECIALLY AGAINST TRICHOMONAS VAGINALIS, IN WARMBLOODED ANIMALS.

United States Patent ,--2-(5-NITRO-2-FURYL)-4-AMINO-THIENO[3,2-d]

PYRIMIDINES AND SALTS THEREOF Eberhard Woitun and Wolfgang Reuter,Biberach (Riss),

Germany, assignors to Boehringer Ingelheim G.m.b.H., Ingelheim/Rhein,Germany No Drawing. Filed Nov. 18, 1970, Ser. No. 90,841 Claimspriority, application Germany, Nov. 26, 1969,

P 19 59 403.7; Oct. 16, 1970, P 20 50 814.9,

Int. Cl. C07d 99/06 US. Cl. 260-256.5 R 11 Claims ABSTRACT on THEDISCLOSURE Compounds of the formula wherein R is hydrogenor methyl, an

R is amino, (alkyl of 1 to carbon atoms)-amino, di-

(alkyl of 1' to 4 carbon atoms)-amino, (monohydroxyalkyl of 2 to 5carbon atoms)-amino, (2,3-dihydroxy-npropyl)-amino, (alkoxy of 1 to 2carbon atoms-alkyl of 1 to 3 carbon at0ms)a.miu0, N-(w-hydroxy-al-kyl of2 to 3 carbon atoms)N-(alkyl of 1 to 4 carbon atoms)- amino,N-methyl-D-glucamino, di-(hydroxy-alkyl of 1' tion salts thereof; thecompounds as well as their salts are useful as bactericidal agentsagainst grarnpositi've rand gramnegative bacteria, as fungicides and astrichomonacides, especially against Trichomonas vaginalis, inwarmblooded animals.

This invention relates to novel 2-(5-nitro-2'-furyl)-4-amino-thieno[3,2-d1pyrimidines and non-toxic pharmacologicallyacceptable acid addition salts thereof, as well as to various methods ofpreparing these compounds.

More particularly, the present invention relates to compounds of theformula v 3,661,908 Patented May 9, 1972 wherein R is hydrogen ormethyl, and

R is amino, (alkyl of 1 to 5 carbon atoms)-arnino, di- (alkyl of 1 to 4'carbon atoms).-amino, (monohydroxyalkyl of 2 to 5 carbon atoms)-amino,(2,3-dihydroxyn-propyl)-amino, (alkoxy of 1 to 2 carbon atoms-alkyl of 1to 3 carbon atoms)-amino, N-(w-hydroxy-alkyl of 2 to 3 carbonatoms)-N-(alkyl of 1 to 4 carbon atoms) amino, N methyl D glucamino, di(hy-' droxy alkyl of 1 to 5 carbon atoms) amino, [-(di alkyl of 1 to 2carbon atoms)-amino-alkyl of 2 to 3 carbon atoms]-am ino, (l-methyl 2hydroxy-ethyD- amino, (l-phenyl 2 hydroxyJethyD-amino,(2-hydroxy-S-diethylamino-n-propyl)-amino, (alkanoyl of 1 to 2 carbonatoms)'-amino, chloroacetyl-amino, di-

' chloroacetyl-arnino, (amino-alkyl of 2 to 3 carbon atoms)-amino,(acetyl-amino-alkyl 013.2 to 3 carbon tatoms)-amino, allylamino,anilino, chloroanilino, methylanilino, hydroxyanilino, methoxyanilino,N-methyb' anilino, benzylamino, phenethyl-amino, cyclohexylamino,(hydroxy cyclohexyl) amino, pyrrolidino, piperidino, hydroxy-piperidino,morpholino, thiomorpholino, thiomorpholinoloxide, piperazino,N-methylpiperazino, N hydroxyethyl piperazino, .N-formylpiperazino orN-carbethoxy-piperazino, and non-toxic, pharmacologically acceptableacid addition salts thereof.

The compounds of the Formula I may be prepared by the following methods:

Method A For the preparation of a compound of the Formula I wherein Rhas the meanings recitedabove except (alkanoyl of 1 to 2 carbonatoms)-amino, chloroacetyl-amino and dichloroacetyl-amino, by reacting a2-(5'-uitro-2'- furyl)-thieno[3,-2-d]pyrimidiue of the formula dzNlwherein R, has the same meanings as in Formulal and Z is halogen,mercapto or lower alkyl-mercapto, with an amine of the formula whereinhas the same meanings as R in Formula I except (alkanoyl of 1 to 2carbon atoms)-amino, chloroacetyl-amino' and dichloroacetyl-amino.

The reaction is preferably carried out in the presence I of an inertorganic solvent or suspension agent attemperatures between 20 and C. IfZ in Formula II is halogen, the presence of a hydrogen halide-bindingagent is required.

A polar inert organic solvent, such as an alkanol, .di-v Imethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone orhexamethyl-phosphoric acid triamide, is preferably used as the solventor suspension medium.

-The hydrogen halide-binding agent may be an equimolar amount of aninorganic or tertiary organic base, or also a substantial molar excessof the amine of the Formula III over and above the stoichiometricallyre- H quired amount.

(III) 7 .x I I I 3 a a Method B By reacting a2-(2'-furyl)-4-amino-thieno[3,2-d]py rimidine of the formula 2 whereinR, has the same meanings as in-For'mula'I and Rfhasthdsame meanings as Rin Formula I except anilino and 'phenylalkyl-amino, with a nitratingagent, such as nitric acid, mixtures of nitric'acid and sulfuric acid'ormixtiire'sof nitric acid and acet-ic acid anhydride. In those instanceswhere R ""is a' substituent comprising a free amino orhydroxyl group,the" said amino, or hydroxyl group" must, prior to' the performance ofthe nitrating reaction, be provided with -a protective group, such asloweralkanoyl, pursuant to known methods; after cornpl'etion' -of =the'nitration, the protective group is removed again according to'conventional methods.

n In 'gen'eral, temperatures of to 30 C. are required for=theperformance of the nitration. In some instances the" p'resence of aninert diluent or solvent is of advantage.

Method C v By reacting a 2-(5'-bromo-2-furyl)-4-arnino-thieno- [3,2-d]pyrimidine of the formula 4 Method E For the preparation of a compoundof the Formula I wherein R is a (alkanoyl of l to 2 carbon atoms)-amino,chlorpacetyl-amino or dichloroacetyl-arnino, 'by acylating a2-(S'-nitro-2 -furyl)-4-amino-thieno[3,2-d]. pyrimidine (VII) acceptableacid addition salts .are those formed with hydrochloric acid,hydrobromic acid, sulfuric acid, tartaric acid, adipicacid, fumaricacid, maleic acid, citric acid, 8-chlorotheophylline or thelike.

The starting compounds of the Formula II wherein Z is halogen may beprepared by reacting a S-nitrofuran-Z- iminocarboxylic acid lower alkylester [see W. R. Sher-.

Preferred examples of nitrous acid salts are alkali metal Yr Method D vBy reacting a 2-(5'-carboxy-2-furyl)-4-aminothieno [3,2-d] pyrimidine ofthe formula wherein R and R have the same meanings as ,in Formula I,with nitric acid or a salt of nitric acid inthe;

presence of a mineral acid.

The reaction is performed in the presence of a strong.

mineral acid, such as concentrated sulfuric; acid, which simultaneouslyserves as thesol-vent medium and at temperatures between and +50 C.,preferably at 010 20 CQExamples of especially suitable salts of nitricacid;

are its alkali metal or alkaline earth metals salts.

If R in Formula VI comprises free amino or hydroxyl== groups, these'areprovided with protective groups, such as acyl radicals, prior to the,reaction incustomary-man i. her. After completion of the reaction, theseprotective,

groups are split off again, if desired.

man et al., J. Med, Chem. 8, (1965 with a 3-aminothiophene-2 -carboxylic acid lower alkyl ester (see- German Patent No. 1,055,007), andhalogenating the ,2-(5- nitro-2 -fu'ryl)-4-hydroxy-thieno [3,2 -cl]pyrimidine formed thereby with a'phosphorus oxyhalide, phosphoruspentah'alide' or thionyl halide. I

The, starting compounds of the Formula IV may be prepared by reacting afuran-Z-iminocarbdxylic acid lower alkyl'ester [see A. Pinner, Chem.Ber. 25, 1416 (1-892) witha 3 amino thiophene carboxylic acid lower alkyl'ester to formfa 2 (2'furyl)-4-hydroxy-thieno- [3 ,2 -d]pyrimidine,subsequently halogenating the latter witha" halogenating agent, such asa phosphorus oxy halide," and reacting 'the' corresponding2-(2'-furyl)-4 halo-thieno[3 ,-2-d]pyrimidine-obtained thereby withatamine of the formula R H'wvhere R has the same meanings-as-in'FormulaIV.

' The starting compounds of the- Formula II wherein Z is "mercapto orlower alkyl-me'rcapto may be prepared by rea 'etiiigii -corresponding 2(S-nitro-2-furyl) 4' halothie'no[3,Zd-1pyrimidine"withthiourea and, ifnecessary, subsequentlyalkylating the reaction product with apota'ssium'alcoholate' for example.

The starting compounds of the Formula V maybe prepared by reactingarompound of the Formula IV with a stoichiometric amount of bromine,preferably in the presencenof an organic solvent and of a hydrogenhalidebind-ing .agent'at atemperature between 0 and 30 C.

-5\Suitable"sol vent media are inert's'olvents, such as 1,2-

dichloro-ethane, or polar solvents, such as glacial acetic acid.Anhydrous sodium acetate may be used as the hydrogen halide-bindingagent, for example.

The starting compounds of the Formula VI may, for

example, be preparedby reacting a S-carbalkoxy-Z-cyanosame meanings asin Formula I, and hydrolizing the reaction product in the presence of anacid, such as hydrochloric acid.

The starting compounds of the Formula VII may be obtained by reacting acompound of the Formula II with ammonia.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood,

however, that the invention is not limited solely to the particularexamples given below.

Preparation of starting compounds:

EXAMPLE A 2- (5 -nitro-2-furyl -4-hydroxy-thien0 [3,2-d pyrimidine 18.4gm. (0.1 mol) of ethyl S-nitrofuran-Z-iminocarboxylate and 17.3 gm.(0.11 mol) of methyl 3-aminothiophene-Z-carboxylate were intimatelyadmixed with each other, and the mixture was heated for one hour at 130C. in a flask. -A crystalline substance began to separate out of theclear melt after a short period of time. At the end of the reactionperiod the contents of the flask had completely solidified. The productwas triturated with ether, the mixture was vacuum filtered,and thefilterv from ethyl 5-nitrofuran-2-iminocarboxylate and methy3-amino-5-methyl-thiophene-2-carb oxylate.

'EXAMPLE B 4-chloro-2-( 5 '-nitro-2'-furyl -thieno [3,2-d] pyrimidine- Amixture of 26.3 gm. (0.1 mol) of 2-(5'-nitro-2'-furyl)-4-hydroxy-thieno[3, 2-d] pyrimidine and 100 ml. of

phosphorus oxychloride was refluxed for three hours;

only incomplete dissolution tookplace. The excess phosphorus oxychloridewas distilled in vacuo, and the residue was introduced into ice water.The aqueous mixtu're 'was vacuum filtered, and the filter cake was driedand recrystallized from dioxane. 23.1 gm. (82% of theory) of 4-chloro 2('-nitro-2'-furyl)-thieno[3,2-d] pyrimidine, M.P. 249-250" C., wereobtained.

Analysis.'--C I-I ClN O S; mol. wt. 281.69. Calculated (percent): .C,42.64; H, 5.01; CI, 12.50. Found (percent): C, 42.51; H, 5.09; Cl,12.67.

(a) In analogous fashion 4 chloro 6 methyl-2-(5'- nitro-'2-furyl)-thieno [3,2-d] pyrimidine, M.P. 190-191 C. (recrystallized fromdioxane), was prepared from 6 methyl 2(5'-nitro-2'-furyl)-4-hydroxy-thieno[3,2 d pyrimidine and phosphorusoxychloride.

' EXAMPLE C 4-mercapto-2-(5-nitro-2'furyl)-thieno[3,2-d]

pyrimidine 9.5 gm. (0.125 mol) of thiourea were added to a refluxingsolution of 2.8 gm. (0.01 mol) of 4-chloro-2-(5T-nitro-2-furyl)-thieno[3,2-d] pyrimidine in 100 ml. ofdimethylformamide. Five minutes after the thiourea had been added, theresulting dark solution was cooled to room temperature and thenpouredinto one liter of ice water. The substance which crystallized outwas collected by vacuum filtration, and the filter cake wasrecrystallized from dioxane. 1.5 gm.-(54% of theory) of 4-mercapto-2-(5-nitor-2'-furyl)-thieno[3,2-d]pyrimidine, M.P. 215 C. (decomp.),were obtained.

Analysis. C H N O S mol. wt. 279.30. Calculated (percent): C, 43.00; H,1.81; N, 15.06; S, 22.94. Found (percent): C, 42.90;H, 1.84; N, 15.20;8, 22.75.

EXAMPLE D 4-methylmercapto-2- 5 '-nitro-2'-furyl) -thieno [3,2]

pyrimidine A suspension of 2.8 gm. (0.01 mol) of 4-mercapto-2-(5-nitro-2-furyl)-thieno[3,2-d]pyrimidine in 100 ml. ofdimethylsulfoxide was added to a stirred solution of 0.85 gm. (0.012mol) of potassium methylate in 150 ml. of dimethylsulfoxide at roomtemperature. A red solution was formed, to which 1.7 gm, (0.012.mol) ofmethyl iodide were added dropwise. Thereafter, the resulting reactionmixture was poured into ice water, and the crystalline precipitateformed thereby was collected by vacuum filtration and recrystallizedfrom dimethylformamide. 1.9 gm. (65 of theory) of4-methylmercapto-2-(5-nitro- 2'-furyl)-thieno[3,2-d] pyrimidine, M.P.240 C., were obtained.

Analysis.C H N O S mol. wt. 293.33. Calculated (percent): C, 45.11; H,2.41; N, 14.33; 8, 21.86. Found (percent): C, 45.28; H, 2.50; N, 14.27;S, 21.70.

EXAMPLE E 2- (2'-furyl)-4-hydroxy-thieno[3,2-d] pyrimidine 36.8 gm. (0.2mol) ofethylfuran-Z-iminocarboxylate and 33.0 gm. (0.21 mol) of methyl3-amino-thiophene- 2-carboxylate were dissolved in 60 ml. of xylene, andthe solution was refluxed for 15 hours. Thereafter, the reactionsolution was allowed to cool, and the crystalline precipitate wascollected by vacuum filtration and recrystallized fromdimethylformamide. 19.1 gm. (44% of of theory) 2-(2-furyl)-4-hydroxythieno[3,2-d]pyrimidine, M.P. 260 C., were obtained.

Analysis.C H N O S; mol. wt. 218.24. Calculated (percent): C, 55.0; H,2.77; N, 12.85. Found (percent): C, 55.06; H, 2.81; N, 12.80.

EXAMPLE F 4-chloro-2-(2-furyl)-thieno[3,2-d] pyrimidine A mixture of21.8 gm. (0.1 mol) of 2-(2'-furyl)-4-hydroxy-thieno[3,2-d]pyrimidine and100 ml. of phosphorus oxychloride was refluxed for one hour, whereby aclear solution was formed. Thereafter, the excess phosphorus oxychloridewas distilled off in vacuo, and the residue was introduced into icewater. The crystalline precipitate formed thereby was collected byvacuum filtration, dried and recrystallized from xylene. 19.0 gm. oftheory) of 4-chl0ro-2-(2'-fury1)-thieno[3,2-d] pyrimidine, M.P. 130 C.,were obtained.

Analysis.-C H ClN OS; mol. wt 236.70. Calculated (percent): C, 50.75; H,2.13; N, 11.82. Found (percent): C, 50.87; H, 2.19; N, 11.93.

EXAMPLE G 2-(2'-furyl) -4-morpholino-thieno[3,2-d]pyrimidine 15.0 gm.(0.063 mol) of 4-chloro-2-(2'-furyl)-thien0 [3,2-d] pyrimidine, ml. ofethanol and 30 ml. of morpholine were combined at room temperature. Anexo-. thermic reaction ensued, and a clear solution formed from whiehacrystalline substance precipitated after a short period of time. Theresulting reaction mixture was refluxed for 30 minutes, then cooled andpoured into water, and the precipitate formed thereby was collected byvacuum filtration, Washed with water and recrystallized from ethanol.15.0 gm. (83% of theory) of 2-(2'-furyl)-4-morpholino-thieno[3,2-d]pyrimidine, M.P. 140 C., were obtained.

Analysis.C H N O S; mol. wt. 287.34. Calculated (percent): C, 58.50; H,4.56; N, 14.63. Found (percent): C, 58.63; H, 4.64; N, 14.50.

The following compounds were prepared in analogous manner:

(a) 2-(2'-furyl)-4-[(B acetylamino-ethyl) amino]-thieno[3,2-d]pyrimidine, M.P. 204205 C. (recrystallized from doixane),from 2-(2-furyl)-4-chloro-thieno [3,2-d] pyrimidine andN-acetyl-ethylenediamine.

(b) 2-(2'-furyl)-4-methylamino thieno[3,2-d]pyrimidine, M.P. 131 C.(recrystallized from ethyl acetate/petroleum ether), from 2-(2-furyl)-4chlorothieno[3,2-d]pyrimidine and methylamine.

(c) 2-(2'-furyl)-4-[(B-methoxy ethyl)-amino]-thieno [3,2-d]pyrimidine,M.P. 117-118 C. (recrystallized from gasoline), from2-(2-furyl)-4-chloro-thieno[3,2-d] pyrimidine and(fl-methoxy-ethyD-amine.

(d) 2-(2-furyl)-4-[(fi-hydroxy-n-propyl-amino]thieno [3,2-d1pyrimidine,M.P. 136137 C. (recrystallized from 7 ethyl acetate/ petroleum ether),from 2-(2'-furyl)-4-chloro-thieno[3,2-d] pyrimidine and(fl-hydroxy-n-propyl) amine.

(e) 2-(2'-furyl)-4-[( S-hydroxy-ethyl) amino]-thieno [3,2-d] pyrimidine,M.P. 182-183 C. (recrystallized from ethyl acetate/petroleum ether),from 2-(2'-furyl)-4-chloro-thieno[3,2-d]pyrimidine and(B-hydroxy-ethyD-amine.

(f) 2-(2-furyl)-4-[(B,y dihydroxy-n-propyl)amino]-thieno[3,2-d]pyrimidine, M.P. 119-121 C. (recrystallized from ethylacetate) from 2-(2-furyl)-4-chl0rothieno[3,2-d]pyrimidine and(B,'y-dihydroxy-n-propyl)- amine.

(g) 2-(2-furyl)-4 amino thieno[3,2-d1pyrimidine, M.P. 224225 C.(recrystallized from ethyl acetate), from2-(2'-furyl)-4-chloro-thieno[3,2-d]pyrimidine and ammonia.

EXAMPLE H 2- 2-furyl 4-[ B-acetoxy-ethyl) -amino] -thieno [3 ,2-dpyrimidine A mixture of 2.6 gm. (0.01 mol) of 2-(2'-furyl)-4-(p-hydroxy-ethyU-amino] -thieno 3,2-d] pyrimidine and 20 ml. of aceticacid anhydride was heated for 90 minutes at 70 C. Thereafter, theresulting blue solution was tion of 1.6 gm. (0.01 mol) of bromine in 20ml. of glacial acetic acid were added to a solution of 2.9 gm. (0.01

dine in glacial acetic acid, and the resulting;.mixture was allowed tostand for 30 minutes more at 20 C. The reaction mixture was thereafteradmixed with water, and the aqueous mixture was extracted three timeswith chloroform. The extract solutions were combined, washed with water,dried over sodium sulfate and evaporated in vacuo. The residue waspurified by column-chromatography on silicagel (particle size 0.2-0.5'mm.), using a mixture of benzene and acetone (8:2) as the flow agent.

0.95 gm. (26% of theory) of 2-(5'-bromo-2"-fu'ryl) 4morpholino-thieno[3,2-d]pyrimidine, M.P. 145-146 C., were obtained.

lated (percent): C, 45.92; H, 3.30; N, 11.47. Found (percent): C, 46.04;H, 3.38; N, 11.31. t

The following compounds were prepared in analogous manner:

(a) 2 bromo 2'-furyl)-4-methylamino-thieno [3,2-d]pyrimidine, M.P.144146 C., from 2-(2'-furyl) 4-methylamino-thieno [3,2-d] pyrimidine andbromine.

(b) 2 (5 bromo 2' furyl) 4[(fi-methoxyethyl)-amino]thieno[3,2-d]pyrimidine, M.P. 135-l36 C., from2 (2' furyl) 4 [(fi-mcthoxy-ethyl)-amino]- thieno[3,2-d] pyrimidine andbromine.

(c) 2 (5 bromo 2' furyl) 4 8 hydroxy-npropyl) amino] thieno[3,2d]pyrirnidine, M.Pf154- 155 C., from 2 (2 furyl) 4 [(fi-hydroxyn- 8npropyl) amino] thieno[3,2-d]pyrimidine, M.P. 148- 150 C., from 2 (2furyl) 4 [(53 dihydroxy-npropyl)-amino]-thieno[3,2-d]pyrimidine, M.P.148-150 C. from 2-(2'-furl)-4-[fly-dihydroxy-n-propyl)-amino]-thieno[3,2-d]pyrimidine and bromine.

(f) 2 (5' bromo 2' furyl) 4 amino thieno [3,2 d]pyrimidine, M.P. 240 C.(decomp.), from 2-(2'- furyl) 4 amino thieno[3,2-d] pyrimidine andbromine.

EXAMPLE I A mixture of 1.3 gm. (0.006 mol) of 2-(2-furyl)-4-amino-thieno[3,2-d ]pyrirnidine and 20 ml. of acetic acid anhydried washeated for minutes at C. Thereafter, the resulting clear solution wasevaporated in vacuo, and the residue was recrystallized from acetone.1.4 gm. (90% of theory) of 2-(2-furyl)-4-acetylamino-thieno[3,2-d]pyrimidine, M.P. 173174 C., were obtained.

Analysis.C H N O S; mol. wt. 259.29. Calculated (percent): C, 55.63; H,3.50; N, 16.21. Found (percent): C, 55.70; H, 3.58; N, 16.13.

EXAMPLE K 2-(5'-methoxycarbonyl-2'-furyl)-4-hydroxy-thieno[3,2-d]pyrimidine 1.8 gm. (0.01 mol) of5-carbomethoxyfuran-2-iminocarboxylic acid methyl ester (M.P. 8283 C.;prepared from 5-carbomethoxyfuran-Z-Carbonitrile, methanol andhydrochloric acid) and 1.7 gm. (0.11 mol) of3-aminothiophene-Z-carboxylic acidmethyl ester were intimately admixedwith each other, and the mixture washeated for 4 hours at ISO-160C.,After some time of heating, a crystalline substance began toseparateout of the clear molten mass, and at the end of the reactiontime the contents of the flask had completely solidified. The. productwas tr'iturated with ethanol, the mixture was vacuumfiltered, and thefilter cake was recrystallized from dimethylformarriide, yielding 1.6gm. (58% of theory) of 2"- (5' methoxycarbonyl 2' furyl) 4hydroxythieno[3,2-d'1pyrimidine, M.P. 300 C.

Analysis."C H -N O S; mol. wt. 276.28. Calculated (percent): C, 52.16; H,,.2.92; N, 10.14. Found'(percent): C, 52.03; H, 2.99; N, 10.26.

EXAMPLE L- i I 2- (5 '-me'thoxycarbonyl=2'-furyl) -4-ch10r -thino[3,2-d] pyrimidine A mixture consisting of 2.8 gm. (0.01 mol) of 2-(5'-methoxycarbonyl 2' furyl) 4-hydroxy-thione[3,2-d] pyrimidine and 20 m1.of phosphorus oxychloride was refluxed for 90 minutes, wherebyeverything went into solution. Thereafter, the excess phosphorusoxychloride was distilled off invacuo, and the residue was decomposed inice water. The crystalline precipitate was collected by vacuumfiltration, dried and recrystallized from a mixture of dimethylformamideand ethanol, yielding 2.1 gm. (71% of theory) .of2-(5'-methoxycarbonyl-2'-furyl)-4- chloro-tln'eno[3,2-dlpyrimidine, M.P.234- C.

Analy sis. C H ClN O S; mo'ljwt. 294.73. Calculated (percent): C, 48.90;H, 2.38; 'N, 16.29; Cl. 12.03. Found (percent): C, 50.00; H, 2.41; N,16.18; Cl, 11.91.

EXAMPLE M 2-( 5 '-carboxy-2"-'furyl)-4-morpholino-thieno [3 2-dpyrimidine (a) A mixture consisting of 2.9 gm. (0.01 mol) of 2 (5'methoxycarbonyl 2' -'furyl) 4 chloro-thieno [3,2-d]pyrimidine and 20 ml.of morpholine was heated for one hour at 100 C. Thereafter, the reactionsolution was admixed with water, the precipitate formed thereby wascollected by vacuum filtration, and the filter cake was washed withwater and recrystallized from ethanol, yielding 2.9'gm. (72% of theory)of 2-(5 "-carboxymorpholido.-'

2 furyl) 4 morpholino-thieno[3,2-d]pyrimidine, M.P. 225-227 C. 1

(b) A mixture consisting of 2.9 gm. of 2-(5-carboxymorpholido-2'-furyl)4 morpholino-thieno[3,2-d]pyrimidine and 15 ml. of concentratedhydrochloric acid was refluxed for 2 hours. Thereafter, the reactionsolution was cooled and then admixed with an equal volume of water, theprecipitate formed thereby was collected by vacuum filtration, and thefilter cake was washed with a small amount of ice water andrecrystallized from methanol, yielding 1.8 gm. (78% of theory) of2-(5-carboxy- 2'-furyl 4 morpholino-thieno [3,2-d]pyrimidine,M.P. 295 C.(decomp).

Analysis.C H N O S; mol. wt. 331.36. Calculated (percent): C, 54.37; H,3.96; N, 12.68. Found (percent): 'C, 54.31; H, 4.07; N, 12.84.

Preparation of end products of the Formula 1:

EXAMPLE 1 4 N- (B-hydroxy-ethyD-ethylamino] -'2-(5 '-nitro-2'furyl)-thieno[3,2-d]pyrimidine by method A A solution of 3.6 gm. (0.036 mol) of2-ethylaminoethanol-(1) .in 10 ml. of dimethylsulfoxide wasaddeddropwise to a stirred suspension of 5.0 gm. (0.018 mol) of4-chloro-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine in 50 m1. ofdimethylsulfoxide at 80 C. Thereafter, the reaction mixture was stirredfor one hour at'80 0, whereby a clear solution was ,formed which wasallowed to cool.

The coolsolution was poured into water, the precipitate formed thereby.was collected by vacuum filtration, and the filter. cake was washed withwater and recrystallized from a mixture of dimethylformamide andethanol. 4.6.

gm. (74% of theory) of 4-[N-(fi-hydroxy-ethyl)-ethylamino] 2(-nitro-2'-furyl) thieno[3,2-d] pyrimidine, M.P. 207-208 C.,.of theformula OzNL if i EXAMPLE 2' Using a procedure analogous to thatdescribed in Example 1, 4 amino2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine, MJP. 300 C.(recrystallized from dirnethylformamide), of the formula was preparedfrom 4-chloro-2-(5'-nitro-2-furyl)-thieno [3,2-d] pyrimidine andammonia.

EXAMPLE 3 Using a procedure analogous to that described in Example 1,4-methylamino 2 (5'-nitro-2'-furyl)-thieno [3,2-d1pyrimidine, M.P.263264 C. (recrystallized from cthanol/dimethylformamide), of theformula HN-CH;

was prepared from 4-chloro-2-(5'-nitro-2-furyl)thieno [3,2d]pyrimidineand methylamine.

EXAMPLE 4 Using a procedure analogous to that described in Example l,4-ethylamino-2-(5-nitro-2'-furyl)-thieno[3,2-d]

pyrimidine, M.P. 178-179" C. (recrystallized frommethanol/dimethylformamide), was prepared from 4-chloro-2-(5-nitro-2-furyl) thieno3,2-d]pyrimidine and ethylamine.

EXAMPLE 5 Using a procedure analogous to that described in Example 1, 4isopropylamino-2-(5'-nitro-2'-furyl)-thieno [3,2-d1pyrimidine, M.P. 197C. (recrystallized from ethanol), was prepared from4-chloro-2-(5'-nitro-2'-furyl)-thieno[3-,2-d] pyrimidine andisopropylamine. v

EXAMPLE 6 ehtanol), was prepared from 4-chloro-2-(5'-nitro-2'furyl)-thieno[3,2 -d] pyrimidine and n-butylamine.

EXAMPLE 7 Using a procedure analogous to that described in Example 1, 4n amylamino-Z-(5'-nitro2'-furyl)-theno [3,2-d]pyrimidine, M.P. 141.142C. (recrystallized from ethanol/water), was prepared from4-chloro-2-.(5'-nitro- 2"-furyl) thieno[3,2-d]pyrimidine andn-amylamine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1,4-allylamino 2 (5'-nitro-2 furyl)-thieno[3,2-d] pyrimidine, M.P. 191-193C. (recrystallized from ethanol), of the formula -was .prepared from4chloro-2-(5-nitro-2'-furyl)thieno [3,2 -d]pyrimidine and allylamine.

I EXAMPLE 9 .Using a procedure analogous to that described in Example 1,4- dirnethylamino-2-(5'-nitro-2'-furyl)-thieno[3,2-d] pyrmudme, M.P.256-258 C. (recrystallized from dimethylformamide), of the formula OzNlI 0 was prepared from 4-chloro-2-(5'-nitro 2'-furyl)-thieno Using aprocedure analogous to that described in Example 1,4-(B-hydroxyethyl-amino) 2 (5'-nitro-2'-furyl)- 11 1 athieno[3,2-d]pyrimidine, M.P. 174175 C. (recrystallized from ethanol),of the formula was prepared from 4-chloro-2-(5-nitro-2f-furyl)-thieno[3,2-d] pyrimidine and fi-hydroxyethyl-amine. H r

EXAMPLE-12' Using a procedure analogous to that described in Exam ple l,4-[(3' hydroxy p propyl)-amino]-2-(5-nitro-"-fu'ryl)-thieno[3,2-d]pyrimidine, M.P. 180-l81 C. (recrystallized fromethanol), was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno[3,2-d] pyrimidine and 3-arnino-1-propanol.t EXAMPLE 13 Using a procedureanalogous to that described in'Exam-' ple1, 4-[(4'-hydroxy n butyl)-amino]-2-(5-nitro-2"-furyl)-thieno[3,2-d1pyrimidine, M.P. l65166 C. (recrystallized frommethanol/water), was prepared from 4- chloro 2 (5-nitro 2'furyl)-thieno[3,2-d]pyrimidine and 4-amino-1-butanol. v

EXAMPLE 14 7 Using a procedure analogous to that described in Example 1,4- ['(5'-hydroxy n pentyl)-amino]-2-(5-nitro-2"- furyl)-thieno[3,2-d]pyrimidine, M.P. 137-138 C. (recrystallized from ethanol/water), wasprepared from 4 chloro 2 (5'-nitro 2' furyl)-thieno[3,2-d1pyrirriidine'and S-amino-l-pentanol.

EXAMPLE 15 HN oH-oH1ocHQ f v was prepared from 4-chloro-2-(5'-nitro-2'furyl) thieno [3,2-d] pyrimidine and fi-methoXyethyl-amine.

EXAMPLE 18 Using a procedure analogous to that described inErtarn} ple1, 4-[(2'-ethoxy-ethy1)-amino] 2 nitr'o'-;2 "-fur-" tallized fromethanol/Water), was prepared-from 4'-'chloro 2 (5'-nitro-2'-furyl)-thieno[3,2-d] pyrimidine and 2- ethoxyethyl-amine. 7

EXAMPLE 19 Using a procedure analogous to that described in Example 1,4-[(3-methoxy-n propyl)-amino]-2(5"-nitro-2"-furyl)-thieno[3,2-d]pyrimidine, M.P. 1333-134 C. (recrystallized frommethanol/water), was prepared from pyrimidine and'(3-rnethoxy-n-propyl)-amine. 1 EXAMPLE 20 Using aprocedure analogous tothat described in-Example l, 4-[N-(p-hydroxy-ethyl)-methylamino] 2 (5'-nitro-2'-furyl )-thi eno [3,2-d] pyrimidine, M.P. 204-205 C.(recrystallized from ethanol/dimethylformamide), was prepared from 4chloro-2-(5'-riitro 2-furyl)-thieno[3,2- dJpyrimidine and-N-(fl-hydroxy-ethyl) methylamine,

EXAMPLE 21 EXAMPLE 22 Using a procedure analogous to that described inEx ample 1, l4- [N-(v-hydroxy-n propyl) -methylamino] -2- 5' nitro-2'-furyl )-thieno [3,2-d]pyrirnidine, M. P,-. I 15'41'5 5 C..(recrystallized from ethanol),-was prepared from 4.-

chloro- 2-.(5nitro-2 -furyl) thieno[3,2-d]pyrimidine and EXAMPLE 23Using a procedure analogous to thatdescribed in Example 1,4(N-rnethyl-D-glucamino)-2-(5-nitro-2-furyl)- thieno[3,2-d]pyrimidine,M.P. 16-168 C. (recrystallized from water), of the formula I .O NL o KNomgn-crrz-pikcn orrgcu-onzoH on H OH- was prepared from4-chloro-2-('-nitro-2-furyl)-thieno [-3,2-d]pyrmidine andN-methylsD-glucamine.

Using a procedure analogous, torthat described in Example 1, 4- [bis-(p-hydroxy-ethyl -amino] -2- 5 '-nitro-2- (recrystallized from ethanol),of the formula Wasprepared from 4-chloro-2-(5f-nitro 2'-fury 1)-thieno 4[3,2-d1pyrirriidine. and bis-(B-hydroxy-ethyU-amine.

EXAMPLE 25 5 Using a procedure analogous to that described in Example 1,4-[N-(fl-hydroxy-ethyl)-N-('y-hydroxy-n-propyl)-arnino]-2-(5-nitro 2furyl)-thieno[3,2-d [pyrimidine, M.P. 197-198 C. (recrystallizedfronimethanol/ dimethylformamide), was prepared from 4-chloro-2-(5-nitro 2' furyl)-thieno'[3,2 d]pyrimidine and 3-[(fi-hydroxy-ethyl)-amino]-1-propanol.

' EXAMPLE 26 Using a procedure analogous to that described in Example 1,4-[bis-('y-hydroxy-n-propyl)-amino]-2-(5'-nitro-2-furyl)-thieno[3,2-d]pyrimidine,M.P. 188-189 C;

(recrystallized from ethanol), was prepared from '4-chloro2-(5'-nitro-2'-furyl) thieno[3,2-d]pyrimidine andbis-('y-hydroxy-n-propyl)-amine.

EXAMPLE 27 Using a procedure analogous to that described in EX",

ample 14-[bis-(5-hydroxy-n-pentyl)-amino]-2-(5"-nitro-2"-furyl)-thieno[3,2-d1pyrimidine,M.P. 114-115" C. (recrystallized from ethanol/ water), was prepared from4-chloro-2-(5'-nitro-2furyl)thieno[3,2-d]pyrimidine andbis(5-hydroxy-n-pentyl)-amine.

EXAMPLE 28 (recrystallized from acetone), was prepared from 4-vchloro-2-(5-nitro-2-furyl)-thieno[3,2 d] pyrimidine andbis-(Z-hydroxy-n-propyl)-amine.

EXAMPLE 30 Using a procedure analogous to that described in Example 1,4-[bis-(fl-methoxy-ethyl)-amino]-2-(5'-nitro-2-furyD-thieno[3,2d]pyrimidine, M.P. 128-129 C. (recrystallized frommethanol), of the formula was prepared from 4-chloro-2-(5-nitro-2'-furyl)-thieno [3,2-d1pyrimidine andbis-(B-methoxy-ethyU-amine.

EXAMPLE 31 Using a procedure analogous to that described in Example 1, 4cyclohexylamino-Z-(-nitro-2-furyl)-thieno [3,2-d1pyrimidine, M.P.183-184" C. (recrystallized from ethanol), of the formula was preparedfrom 4-chloro-2-(5'-nitro2'-furyl)-thieno [3.2-d] pyrimidine andcyclohexylamine.

EXAMPLE 32 Using a procedure analogous to that described in Example l,4-piperidin0-2- 5--nitr0-2-furyl -thieno 3,2-d] pyrimidine, M.P. l96198C. (recrystallized from eth anol), of the formula was prepared from4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2-d]pyrimidine and piperidine.

EXAMPLE 33 Using a procedure analogous toj that described in Ex- 7ample, 1, 4 (3' hydroxypiperidino)-2-(5"-nitro-2"-furyl)thieno[3,2-d1pyrimidine,M.P; 214215 C; (recrystallized fromethanol),o the formula v wasaprepared from4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2d]pyrimidine and 3hydroxy-piperidine.

EXAMPLE 34 Using a procedure analogousto that described in Example 1,4-(4' hydroxy piperidino) 2 (5 nitro-2'- furyl)-thieno[3,2 d]pyrimidine,M.P. 211-2129 C. (recrystallized from ethanol/dimethylformamide), wasprepared from 4 chloro-2-(5'-nitro-2'-furyl)-thieno[3,2-d]

pyrimidine and 4-hydroxy-piperidine.

EXAMPLE 35 Using a procedure analogous to that described in Example 1,.4-"(=N methyl piperazino) 2 nitro-2"- furyl)-thieno[3,2-d]pyrimidine,M.P. 178179 C. (recrystallized from ethanol), of the formula wasprepared from 4-chloro-2-(5'-nitro-2-furyl)-thien0 [3,2-d] pyrimidineand N-m'ethyl-piperazine.

EXAMPLE 36 Using a procedure analogous to that described in Example 1,4-[N-(;8-hydroxy-ethyl)-piperazino] 2 (5"- nitro-2"-furyl)-thieno[3,2-d]pyrimidine, M.P. 186-187 C. (recrystallized from ethanol), of theformula dlpyr'imidine MP. 203-20? '0. (recrystallized fromdimethylformamide'l of the formula OzNl was prepared from 4chloro-2-(5-nitro-2'-fury1)-thieno [3,2-d].pyrimidine.tand piperazine. I a

" EXAMPLE 42 Using a procedure analogous to that described in- Example1, 4 (N' formyl-piperazino)-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine, M.P. 27-8? 0. (recrystallize'd fromdii'nethylformamide)? of the formula O=CH was prepared from4-chloro-2-(5'-nitro 2'-furyl)-thieno- [3,2-d] pyrimidine and N-formy1-piperazi ne.

EXAMPLE 43" was prepared from -4-chloro-2-(5'-nitro-2'-furyl)-thieno-[3,2-d] pyrimidine and N-carbethoxy-piperazine.

EXAMPLE 44 Using a procedureanalogous to thatvdescribed in Example 1,4-benzylamino-2-(5-nitro-2'-furyl)-thieno[3,2-

d]pyrirnidine, M.P. 162 C. (recrystallized from ethyl was prepared from4-chlorof2-(5-nitro 2' fury1)iliieho [3 2-d]pyrirnidine and N-(flhydroxy ethyl)-piperazine: Using a procedure analogous to that described inExample 1, 4-pyrrolidino-2-(5-nitro-2'-furyl)-thieno[3,2-d]- pyrimidine,M.P. 203-204 C. (recrystallized from etha- 1101), of the formula oar-lif was prepared from 4-chloro-2-(5-nitro-2rfnryl);thieno-[3,2-d1pyrimidine and pyrrolidine.

EXAMPLE 38 40 Using a procedure analogous to that de'scribedfin Example1, 4 7 [(fl-dimethylamino ethyl)gamin J Z-(SQ;.nitro-2'-furyl)-thieno[3,2-d]pyrimidine, My; 144+. l4"5, C.-(recrystallized from methanol/water), of -the formula 1IN-CHzCHr N(CH:)1

was prepared from 4-chloro-2 (5-nitro-2.'-furyl)-thieno-[3,2-d1pyrimidine and S-dimethyIaminO ethyD-amine.

1; EXAMPLE 39 Using a procedure analogous to that described in ExampleI, 4- [(fl-diethylamino-ethyl -amino] -2- 5 '-nitro-2'-furyl)-thieno[3,2-d]pyrimidine, M.P. 103-104 C. (re- 0 crystallized fromethanol/ water), was prepared from 4 chloro-2-(5'nitro-2'-furyl)-thieno[3,2-d] pyrimidine and(,B-diethylamino-ethyl)-amine.

EXAMPIJE 40 Using a procedure analogous to that described in Example I,4 [(-y-diethylamino-n-propyl)amino]-2-(5'- nitro2-furyl)-thieno[3,2-d1pyrimidine, M.P. 1 27 1}? (recrystallized fromethanol/water), was preparedfrorn' 4-chloro-2- (5 '-nitro-2-furyl-'thienb 3,2-d] pyrimidi'neand 7O -diethylaminom-propyl -amine.

EXAMPLE 41 I Using a procedure analogous to that described in Example 1,4-piperazino-2-(5-nitro-2-furyl)-thieno[3,2-

acetate), of the formula irrr-om-oui,

1 7 EXAMPLE 45 Using a procedure analogous to that described in Examplel, 4 (p phenethyl-amino)-2-(5'-nitro-2'-furyl)- thieno[3,2-d]pyrimidine, M.P. 165 C. (recrystallized from ethylacetate), wasprepared from 4-chloro-2-(5'= nitro-2'-furyl)-thieno[3,2-d1pyrimidineand p-phenethylamine.

EXAMPLE 46 Using a procedure analogous to that described in Example 1,4-anilino-2-(5-nitro-2'-furyl)-thieno[3,2-d] pyrimidine, M.P. 162-164"C. (recrystallized from ethyl acetate), of the formula was prepared from4-chloro-2-(5'-nitro-2-furyl)thieno [3,2-d]pyrimidine and aniline.

EXAMPLE 47 Using a procedure analogous to that described in Example 1,4-(p-chloro-anilino)-2-(5-nitro-2'-ifuryl)-thieno [3,2-d1pyrimidine,M.P. 262 C. (recrystallized from ethyl acetate), of the formula s HNQ-Clwas prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2-d]pyrimidine and p-chloro-aniline.

EXAMPLE 48 Using a procedure analogous to that described in Example 1,4-(o-chloro-anilino)-2-(5-nitro-2'-furyl)thieno [3,2-d]pyrimidine, M.P.23 8240 C. (recrystallized from ethyl acetate), was prepared from4-chloro-2-(5'-nitro-2'- furyD-thieno[3,2-d1pyrimidine ando-chloro-auiline.

EXAMPLE 49 Using a procedure analogous to that described in 'Example 1,4-(m-chloro-anilino)-2-(5'-nitro-2'-furyl)thieno [3,2-d]pyrimidine, M.P.257-258 C. (recrystallized from ethyl acetate), was prepared from4-chloro-2-(5-nitro-2'- furyl) -thieno [3,2-d] pyrimidine andm-chloro-aniline.

EXAMPLE 50 Using a procedure analogous to that described in Example l, 4(p methoxy-anilino)-2-(5'-nitro-2'-furyl)- thieno[3,2-d]pyrimidine, M.P.2l1212 C. (recrystal lized from ethyl acetate), of the formula OzN Usinga procedure analogous to that described in Example 1,4-(pmethyl-anilino)-2-(5'-nitro-2'-fury1)-thieno 18 [3,2-dlpyrimidine,M.P. 224-226 C. (recrystallized ifrom ethyl acetate), of the formulaOrri ZEN-@CH;

was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2-d]pyrimidine and p-methyl-aniline.

EXAMPLE 52 Using a procedure analogous to that described in Example 1,4-(p-hydroxy-anilino)-2-(5'-nitro-2;-fury1)-thieno [3,2-d] pyrimidine,M.P. 268 C. (recrystallized from ethyl acetate), of the formula all inu-on was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2-d]pyrimidine and p-amino-phenol.

EXAMPLE 5 3 Using a procedure analogous to that described in Ex ample 1,4- (m-hydroxy-anilino)-2-(5'-nitro-2'-furyl)- thieno[3,2-d] pyrimidine,M.P. 282 C. (recrystallized from ethyl acetate), was prepared from4-chloro-2-(5- nitro-2'-furyl)-thieno[3,2-d]pyrimidine andn-aminophenol.

EXAMPLE 54 Using a procedure analogous to that described in Example 1,4-(o-hydroxy-anilino)-2-(5'-nitro-2'-furyl-thieno [3,2-d] pyrimidine,M.P. 244 C. (recrystallized from ethyl acetate), was prepared from4-chloro-2-(5'-nitro-2'- furyl) -thieno[3,2-d]pyrimidine ando-amino-phenol.

EXAMPLE 55 Using a procedure analogous to that described in Example 1,4-(N-methyl-anilino) 2-(5-nitro-2-furyl)-thieno- [3,2-d]pyrimidine, M.P.201-202 C. (recrystallized from ethyl acetate), of the formula oaN L wasprepared from 4 chloro-Z-(5'-nitro 2'-furyl)-thieno- [3,2-d] pyrimidineand N-methyl-aniline.

EXAMPLE 56 Using a procedure analogous to that described in Example 1,4-(fl-hydroxyethyl-amino)-6-methyl-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine,M.P. 189190 C. (recrystallized from ethanol), of the formula wasprepared from 4-chloro-6-methyl-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine and 2-amino-ethanol.

19 EXAMPLE 57 Using a procedure analogous to that described in Example1, 4-[his(fl-hydroxy-ethyD-amino] 6 methyl 2- ('-nitro-2'-furyl -thieno[3,2-d] pyrimidine, M.P. 187- EXAMPLE 64 Using a procedure analogous tothat described in Example 1,4-[(,li-hydroxy-B-phenyl-ethyl)-amino]-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine,M.P. 188-189 C.

188 C. (recrystallized from ethanol), was prepared from 5(recrystallized from ethanol), of the formula 4-chloro-6-methyl 2(5'-nitro-2-furyl)-thieno[3,2-d] pyrimidine andbis-(,B-hydroxy-ethyl)-amine.

EXAMPLE 5 8 Using a procedure analogous to that described in Example 1,4-amino-6-methyl-2-(5-nitro-2'-furyl)-thieno- [3,2-d]pyrimidine, M.P.300 C. (recrystallized from dimethylformamide), was prepared from4-chloro-6-methyl-2-(5-nitro-2'-furyl)-thieno[3,2-d] pyrimidine andammonia.

EXAMPLE 59 Using a procedure analogous to that described in Example 1,4-methylamino-6-methyl-2-(5-nitro-2-furyl)- thieno[3,2-d]pyrimidine,M.P. 231-233 C. (recrystallized from ethanol), was prepared from4-chloro-6-methyl-2-(5' nitro 2' furyl)-thieno[3,2-d]pyrimidine andmethylamine.

EXAMPLE 60 Using a procedure analogous to that described in Example 1,4- (2,3 '-dihydroxy-n-propyl) -arnino] -6-methyl- 2-(5"-nitro 2" furyl)thienol[3,2-d] pyrimidine, M.P. 210-211 C. (recrystallized fromethanol), of the formula Ml \o l wcm HN-CHa-CH-CHaOH was prepared from4-ch1oro-6-methyl-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine andl-amino-2,3-propanediol.

EXAMPLE 61 Using a procedure analogous to that described in EX- ample 1,4-[(/3 methoxy-ethyl) amino] 6 methyl-2- (5-nitro-2-furyl)thieno[3,2-d]pyrimidine, M.P. 174- 175 C. (recrystallized fromdimethylformamide methylene chloride), was prepared from4-chloro-6-methyl-2- (5- nitro-2-furyl)-thieno[3,2-d]pyrimidine and Bmethoxyethyl-amine.

EXAMPLE 62 was prepared from 4-chloro-2-(5'-nitro-2-furyl)-thieno[3,2-d1pyrimidine and 1-hydroxy-2-amino-propane.

l OnN HlX-CHz-CHOH was prepared from4-chloro-2-(5'-nitro-2'-furyl)-thieno [3,2-d]pyrimidine and(2-hydroxy-2-phenyl-ethyl)-amine.

EXAMPLE Using a procedure analogous to that described in Example 1,4-[(2-hydroxy-cyclohexyl)-amino]-2-(5"-nitro-2"- furyl)-thieno[3,2-d]pyrimidine, M.P. 137-138 C. (recrystallized from ethanol/ water), of theformula ic/ f was prepared from 4-chloro-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine and (2-hydroxy-cyclohexyl)-amine.

EXAMPLE 66 Using a procedure analogous to that described in Example 1,4-[(4-hydroxy-cyclohexyl)-amino]-2-(5"-nitro-2"-furyl)-thieno[3,2-d1pyrimidine, M.P. 226-228 C. (recrystallized fromtetrahydrofuran/ water) was prepared from 4-chloro2-(5'-nitro-2-furyl)-thieno[3,2-d] pyrimidine and(4-hydroxy-cyclohexyl)-amine.

EXAMPLE 67 Using a procedure analogous to that described in Example 1,4-thiomorpholino 2 (5' nitro 2 furyl)-thieno [3,2-d]pyrimidine, M.P.205207 C. (recrystallized from ethyl acetate), of the formula 5 wasprepared from 4-chloro-2-(5-nitro-2'-furyl)-thieno [3,2-d] pyrimidineand thiomorpholine.

EXAMPLE 68 Using a procedure analogous to that described in Example 1,4-(thiomorpholino 1 oxide)-2-(5'-nitro-2'-fury1) 21thieno[3,2-d]pyrimidine, M.P. 280 C. (decomp.; recrystallized fromdimethylsulfoxide), of the formula was prepared from4-chloro-2-(5'-nitro-2-furyl)-thieno [3,2-d] pyrimidine and (3dimethylamino n propyl)- amine.

EXAMPLE 70 Using a procedure analogous to that described in Example 1,4-[ (3-diethylamino-2'-hydroxy-n-propyl)-amino]-2-(5"-nitro-2"-furyl)-thieno[3,2-d1pyrimidine, M.P. 150- 152 C.(recrystallized from ethanol/ water), was prepared from 4-chloro 2(5'-nitro-2'-furyl) -thieno[3,2-d] pyrimidine and (3 diethylamine 2hydroxy-n-propyl)- amine.

EXAMPLE 71 4-diethylamino-2- 5 '-nitro-2'-furyl) -thieno [3 ,2-d]pyrimidine by Method A A solution of 0.75 gm. (0.01 mol) of diethylaminein 25 ml.of dimethylsulfoxide was added dropwise to a stirred suspensionof 2.9 gm. (0.01 mol) of 4-methylmercapto-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine in 25 ml. ofdimethylsulfoxide at 120 C. The reaction mixture was then stirred fortwo hours at120 C., whereby methylmercaptan escaped and a clear solutiongradually formed, the solution was allowed to cool and was then pouredinto ice water, the precipitate formed thereby was collected by vacuumfiltration, and the filter cake was washed with water and recrystallizedfrom ethanol. 1.3 gm. (41% of theory) of 4-diethylamino 2 (5nitro-2-furyl)-thieno [3,2-d]pyrimidine, M.P. 128129 C., of the formulaEXAMPLE 72 4-[ (,B-acetylamino-ethyl) -amino]-2-(5'-nitro-2'-furyl)thieno[3,2-d]pyrimidine by Method A A solution of 3.6 gm. (0.036 mol) ofN-acetylethylenediamine in 10 ml. of dimethylsulfoxide was slowly addeddropwise to a stirred suspension of 5.0 gm. (0.018 mol) of4-chloro-2-(5'-nitro 2'-furyl)-thieno[3,2-d] pyrimidine in 50 ml. ofdimethylsulfoxide at C. Thereafter, the reaction mixture was stirred forminutes at 80 C., whereby a clear solution was formed, and allowed tocool. The cool solution was poured into ice water, the precipitateformed thereby was collected by vacuum filtration, and the filter cakewas washed with water and then recrystallized from a mixture of methanoland dimethylformamide. 5.0 gm. (81% of theory) of the compound of theformula HN-OHrCH -H-CLJH N M.P. 241-242 C., were obtained.

Analysis.-C H N O S; mol wt. 347.36. Calculated (percent): C, 48.41; H,3.78; N, 20.16. Found (percent):

C, 48.33; H, 3.80; N, 20.15.

EXAMPLE 73 Using a procedure analogous to that described in EX- ample72, 4- 3'-acetylamino-n-propyl) -amino]-2-(5"-nitro-2-fury1)-thieno[3,2-d]pyrimidine, M.P. 187 C.(recrystallized from ethanol), was prepared from 4-chloro-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine and(S-acetylamino-n-propyl)-amine.

EXAMPLE 74 Using a procedure analogous to that described in Example 1,4- (p-acetylamino-ethyl) -amino] -6-methyl-2-(5-nitro-2-furyl)-thieno[3,2-d]pyrimidine, M.P. 239- 240 C.(recrystallized from dimethylformamide), was prepared from4-chloro-6-methyl-2-(5'-nitro-2.'-furyl)-thieno[3,2-d] pyrimidine andN-acetyl-ethylenediamine.

EXAMPLE 75 4 morpholino-Z-(5'-nitro-2'-furyl)-thien0[3,2-d] pyrimidineby Method B 0.063 gm. (0.01 mol) of nitric acid was added to a solutionof 2.9 gm. (0.01 mol) of 2-(2'-furyl)-4-morpholino-thieno[3,2-d1pyrimidine in 30 ml. of acetic acid anhydride,whereby the nitrate of the starting compound crystallized out, which wascollected by vacuum filtration, Washed with acetic acid anhydride, andthen introduced at room temperature into 30 ml. of concentrated sulfuricacid, while stirring. The mixture was allowed to stand at roomtemperature for five hours, was then poured over ice, and, whileexteriorly cooling, concentrated ammonia was added to the aqueousmixture until its pH had adjusted to 6. A crystalline precipitateformed, which was collected by vacuum filtration and recrystallized oncefrom dioxane and once from dimethylformamide. 1.05 gm. (32% of theory)of the compound of the formula 1 l N OQNL O 23 EXAMPLE 76 Using aprocedure analogous to that described in Example 75, 4-[B-acetylamino-ethyl)-amino] -2-( -nitro-2'- furyl)-thieno[3,2-d]pyrimidine, M.P. 24l242 C. (recrystallized frommethanol/dimethylformamide), was prepared from4-[(B-acetylamino-ethyl)-amino]-2-(2-furyl)-thieno[3,2-d]pyrirnidinenitrate and concentrated sulfuric acid.

EXAMPLE 77 Using a procedure analogous to that described in Example 75,4-acetylamino-2-(5'-nitro-2'-furyl)-thieno[3,2- d]pyrimidine, M.P.259260 C. (recrystallized from acetone), was prepared from4-acetylamino-2-(2'-furyl)-thieno[3,2-d]pyrimidine nitrate andconcentrated sulfuric acid.

EXAMPLE 78 4-[ (,H-amino-ethyl -amino] -2- 5'-nitro-2'-furyl thieno [3,2-d] pyrimidine hydrochloride A mixture consisting of 7.0 gm. (0.02mol) of 4-[(,B- acetylamino-ethyl)-amino] 2 (5-nitro-2-furyl)-thieno[3,2-d1pyrimidine and 75 ml. of concentrated hydrochloric acid washeated for ten hours on a boiling water bath. Thereafter, the resultingclear solution was evaporated to dryness, and the residue wasrecrystallized from aqueous ethanol. 4.0 gm. (59% of theory) of thecompound of the formula HN-OHz-ClL-NIL-HOI M.P. 292 C. (decomp.), wereobtained.

Analysis.-C H N O S-HC1; mol. Wt. 341.79. Calculated (percent): C,42.16; H, 3.54; N, 20.49; C1, 10.38.

Found (percent): C, 42.35; H, 3.64; N, 20.48; Cl, 10.32.

EXAMPLE 79 Using a procedure analogous to that described in Example 78,4-[('y-amino-n-propyl)-amino]-2-(5'-nitro-2-furyD-thieno[3,2-d]pyrimidine hydrochloride, M.P. 300 C. (recrystallizedfrom ethanol), was prepared from 4-[ -acetylamino-n-propyl-amino]-2-(5-nitro-2'- furyl)-thieno[3,2-d]pyrimidine and concentratedhydrochloric acid.

EXAMPLE 80 Using a procedure analogous to that described in Example 78,4- (fi-amino-ethyl -amino -6-methyl-2- 5 -nitro-2-furyl) -thieno 3,2-d]pyrimidine hydrochloride, M.P. 300 C. (recrystallized from water), wasprepared from 4 [(fi-acetylamino-ethyl)-amino] 6-methyl-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine and concentrated hydrochloric acid.

EXAMPLE 81 Using a procedure analogous to that described in Example 78,4[(B-hydmXy-ethyD-amino]-2-(5'-nitro-2-furyl)-thieno[3,2-d]pyrimidinehydrochloride, M.P. 174- 175 C. (recrystallized from ethanol), wasprepared from 4 [(B-acetoxy-ethyl -amino] -2- 5 '-nitro-2'-furyl -thieno[3,2-d1pyrimidine, M.P. 195-197 C. (from methyl eth yl ketone), andconcentrated hydrochloric acid.

EXAMPLE 82 4- (chloroacetyl-amino -2-( 5'-nitro-2'-furyl -thieno [3,2-d]pyrimidine A suspension of 4.0 gm. (0.015 mol) of 4-amino-2-(5'-nitro-2-furyl)-thieno[3,2-d]pyrimidine in 40 ml. of chloroacetylchloride was refluxed for six hours; no dissolution took place. Thereaction mixture was cooled, the

insoluble matter was collected by vacuum filtration, and the filter cakewas thoroughly washed first with chloroform and then with water, driedand recrystallized from methyl ethyl ketone. 2.5 gm. (49% of theory) ofthe compound of the formula M.P. 206-209 C. (decomp.), were obtained.

Analysis.-C H ClN O S; mol. wt. 338.74. Calculated (percent): C, 42.55;H, 2.09; N, 16.54. Found (percent): C, 42.70; H, 2.15; N, 16.45.

EXAMPLE 83 Using a procedure analogous to that described in Example 82,4 (acetyl-amino)-2-(5-nitro-2'-furyl)-thieno- [3,2-d] pyrimidine, M.P.259-260 C. (recrystallized from acetone), was prepared from 4amino-2-(5-nitro-2- furyl)-thieno[3,2-d]pyrimidine and acetyl chloride.

EXAMPLE 84 EXAMPLE 85 Using a procedure analogous to that described inExample 82, 4 (propionyl-amino)-2-(5'-nitro-2'-furyl)- thieno[3,2-d]pyrimidine, M.P. 217-219 C. (recrystallized from'ethanol), was preparedfrom 4-amino-2-(5'-nitro-2'- furyl)-thieno[3,2-d] pyrimidine andpropionyl chloride.

EXAMPLE 86 4-morpholino-2- (5 '-nitro-2'-furyl) -thieno 3,2-d]pyrimidine by Method C 1.05 gm. (0.015 mol) of sodium nitrite were addedin small portions to a solution of 1.8 gm. (0.005 mol) of 2 (5' bromo 2furyl)-4-morpholino-thieno[3,2-d] pyrimidine in 25 ml. of glacial aceticacid, and the reaction mixture was then refluxed for one hour.Thereafter, the resulting clear solution was poured into water, theprecipitate formed thereby was collected by vacuum filtration, and thefilter cake was washed with water, dried and recrystallized fromdimethylformamide. 1.25 gm. (75% of theory) of the same compound as thatobtained in Example 75, M.P. 218-219 C., were recovered.

EXAMPLE 87 Using a procedure analogous to that described in Example 86,4-methylamino-2-(5'-nitro-2'-furyl)-thieno[3, 2-d]pyrimidine, M.P.263-264" C. (recrystallized from ethanol/dimethylformamide), wasprepared from 4- methylamino 2 (5-bromo 2' furyl)-thieuo[3,2-d]pyrimidine and sodium nitrite.

EXAMPLE 88 Using a procedure analogous to that described in Example 86,4 [(B-methoxy-ethyD-amino]-2-(5-nitro- 2 furyl) thieno[3,2-d]pyrimidine,M.P. 15l-152 C. (recrystallized from methanol), was prepared from 4-[([3- methoxy-ethyl) amino] 2 (5 -bromo-2'-furyl)-thieno-[3,2-d]pyrimidine and sodium nitrite.

EXAMPLE 89 Using a procedure analogous to that described in Example 86,4 [(fl-hydroxy-n-propyl)-amino]-2-(5'-nitro- 2' furyl) thieno[3,2-d]pyrimidine, M.P. 192193 C.

25 (recrystallized from ethanol), was prepared from 4-[(flhydroxy npropyl) amino]-2-(5'-bromo-2'-furyl)- thieno[3,2-d]pyrimidine and sodiumnitrite.

EXAMPLE 90 Using a procedure analogous to that described in Example 86,4 [(fi-hydroXy-ethyl)-amino]-2-(5'-nitro-2- furyl)thieno[3,2-d]pyrimidine, M.P. 174-175 C. (recrystallized from ethanol),was prepared from 4-[(18-hydroxy-ethyl) amino] 2 bromo-2'-furyl)-thieno-[3,2-d]pyrimidine and sodium nitrite.

EXAMPLE 91 Using a procedure analogous to that described in Example 86,4 [(Bq dihydroxy-n-propyl)-amino]-2-(5'- nitro 2' furyl)thieno[3,2-d1pyrimidine, M.P. 179- 180 C. (recrystallized frommethanol), was prepared from 4 [(Bn dihydroxy n propyl) amino]-2-(5-bromo 2' furyl) thieno[3,2-d1pyrimidine and sodium nitrite.

EXAMPLE 92 Using a procedure analogous to that described in Example 86,4 amino 2 (5' nitro 2' furyl)-thieno- [3,2-d]pyrimidine, M.P. 300 C.(recrystallized from dimethylformamide), was prepared from4-amino-2-(5'- bromo 2' furyl)-thieno[3,2-d] pyrimidine and sodiumnitrite.

EXAMPLE 93 v 4-(fi-methoxyethyl-amino)-6-methyl-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine by Method B 0.063 gm. (0.01 mol) of 100%nitric acid was added to a solution of 2.9 gm. (0.01 mol) of2-furyl-4-(fi-methoxyethyl-amino) 6 methyl thieno[3,2-d1pyrimidine in 30ml. of acetic acid anhydride. The crystalline nitrate formed thereby wascollected by vacuum filtration, washed with acetic acid anhydride andthen stirred at room temperature into 30 ml. of concentrated sulfuricacid. The mixture was stirred for five hours at 25 C., then poured overice and, while cooling the aqueous mixture, concentrated ammonia wasadded thereto until it had a pH of 6. A crystalline precipitate wasformed, which was collected by vacuum filtration and recrystallized froma mixture of dimethylformamide and methylene chloride, yielding 0.8 gm.(25% of theory) of the compound of the formula N ON i S/CH3 l having amelting point of 174-175 C.

AnaZysis.C I-I N O S; mol. wt. 334.36. Calculated (percent): C, 50.28;H, 4.22; N, 16.76. Found (percent): C, 50.36; H, 4.27; N, 16.70.

EXAMPLE 94 4-amino-2- (5 '-nitro-2-furyl) -thieno [3,2-d] pyrimidine byMethod A A solution of 0.5 gm. (0.03 mol) of ammonia in ml. of ethanolwas added dropwise over a period of an hour to a suspension of 2.8 gm.(0.01 mol) of 4-chloro-2-(5- nitro 2' furyl) ttueno[3,2-d]pyrimidine at60 C., and the resulting reaction mixture was allowed to stand for onehour more at 60 C. Thereafter, the reaction mixture was cooled and thenpoured into 50 ml. of methylene chloride. The precipitate formed therebywas collected by vacuum filtration, thoroughly washed with water, driedand recrystallized from dimethylformamide, yielding 2.0 gm. (76% oftheory) of 4-amino-2-(5-nitro-2-furyl)- thieno[3,2-d1pyrimidine, M.P.300 C.

Analysis.-C H N O S; mol. wt. 262.26. Calculated 26 (percent): C, 45.81;H, 2.31; N. 21.37. Found (percent): C, 45.70; H, 2.38; N, 21.25.

EXAMPLE 95 2- (5 -nitro-2'-furyl) -4-thiomorpholino-thieno [3 ,2-d]pyrimidine by Method B 0.63 gm. (0.01 mol) of nitric acid were added toa solution of 3.0 gm. 0.01 mol) of2-(2-furyl)-4-thiomorpholino-thieno[3,2-d] pyrimidine (prepared from4-chloro- 2-( 2'-furyl)-thieno[3,2-d] pyrimidine and thiomorpholine) in30 ml. of acetic acid anhydride. The nitrate formed thereby wascollected by vacuum filtration, washed with acetic acid anhydride andthen introduced into 30 ml. of concentrated sulfuric acid at roomtemperature, while stirring. The mixture was then stirred at roomtemperature for five hours, thereafter poured over ice and, whilecooling the aqueous mixture, concentrated ammonia was added theretountil it had a pH of 6. The crystalline precipitate formed thereby wascollected by vacuum filtration and recrystallized from ethyl acetate,yielding 0.9 gm. (26% of theory) of2-(5'-nitro-2-furyl)-4-thiom0rpholino-thieno[3,2-d]pyrimidine, M.P.205-207 C.

Analysis.C H N O S mol. wt. 348.41. Calculated (percent): C, 48.26; H,3.48; N, 16.08. Found (percent): C, 48.14; H, 3.49; N, 16.15.

EXAMPLE 96 Using a procedure analogous to that described in Example 95,4-acetamino-2-(5-nitro-2'-furyl)-thien0[3,2-d] pyrimidine, M.P. 259-260C. (recrystallized from acetone), was prepared from4-acetamino-2-(2'-furyl)-thieno [3,2-d]pyrimidine nitrate andconcentrated sulfuric acid.

EXAMPLE 97 4- (morph01ino-2- 5 '-nitro-2'-furyl -thi0no [3,2-d]pyrimidine by Method D 3.3 gm. (0.01 mol) of2-(5'-carboxyl-2'-furyl)-4-morpholino-thieno[3,2-d]pyrimidine weredissolved in 15 ml. of concentrated sulfuric acid, and, while vigorouslystirring the resulting solution, a solution of 0.85 gm. (0.01 mol) ofsodium nitrate in 15 ml. of sulfuric acid, cooled to 0 C., was addedthereto. The reaction mixture was allowed to stand at 20 C. for twohours, was then poured over ice, and the aqueous mixture was neutralizedwith solid sodium bicarbonate and extracted four times with chloroform.The chloroform extracts were combined, washed with water, dried oversodium sulfate, the chloroform was distilled ofi? in vacuo, and theresidue was recrystallized from dimethylformamide, yielding 0.9 gm. (27%theory) of 4-morpholino 2 (5-nitro-2'-furyl)-thieno [3,2-d] pyrimidine,M.P. 218-219" C.

Analysis.C I-I N O S; mol. wt. 332.34. Calculated (percent): C, 50.60;H, 3.64; N, 16.87. Found (percent): C, 50.71; H, 3.69; N, 16.74.

EXAMPLE 98 Using a procedure analogous to that described in Exampic 97,4-methy1amino-2-(5'-nitro-2-furyl)-thieno[3,2-d] pyrimidine, M.P.263-264 C. (recrystallized from ethanol/dimethylformamide), was preparedfrom 2-(5'-carboxy-2'-furyl)-4-methylamino thieno[3,2-d] pyrimidine,sodium nitrate and sulfuric acid.

EXAMPLE 99 Using a procedure analogous to that described in Example 97,4-( ,B-methoxyethyl-amino) -2-( 5 '-nitro-2'-furyl)-thieno[3,2-d1pyrimidine, M.P. 151-152 C. (recrystallized from methanol),was prepared from 2-(5'-carboxy-2'-furyl) -4- (B methoxyethyl-amino-thieno [3,2-d] pyrimidine, sodium nitrate and sulfuric acid.

EXAMPLE 10.0

Using a precedure analogous to that described in Example 97, 4-(5hydroxy-n-propyl-amino)-2-(5'-nitro-2'- furyl)-thieno[3,2-d]pyrimidine,M.P. 192-193 C. (re

crystallized from ethanol), was prepared from 2-(5-carboxy 2' furyl) 4(B-hydroxy-n-propyl-amino)-thieno [3,2-d]pyrimidine, sodium nitrate andsulfuric acid.

EXAMPLE 101 Using a procedure analogous to that described in Example 97,4-(fl-hydroxyethyl-amino)-2-(5'-nitro-2'-furyl)-thieno[3,2-d]pyrimidine, M.P. 174-175 C. (recrystallized from ethanol),was prepared from 2-(5'-carboxy-2'- furyl) 4(fl-hydroxyethyl-amino)-thieno[3,2-d]pyrimidine, sodium nitrate andsulfuric acid.

EXAMPLE 102 Using a procedure analogous to that described in Example 97,4(B,'y-dihydroxy-mpropyl-amino)-2-(5'-nitrofuryl)-thieno[3,2-d1pyrimidine,M.P. 179180 C. (recrystallized from methanol), was prepared from 2-(5'-carboxy 2 furyl)-4-(,8,'y-dihydroxy-n-propyl-amino)- thieno[3,2-d]pyrimidine, sodium nitrate and sulfuric acid.

EXAMPLE 103 Using a procedure analogous to that described in Example 97,4-amino-2-(5-nitro-2-furyl) -thieno [3,2-d1pyrimidine, M.P. 300 C.(recrystallized from dimethylformamide), was prepared from2-(5'-carboxy-2-furyl)- 4-amino-thieno[3,2-d]pyrimidine, sodium nitrateand sulfuric acid.

The compounds according to the present invention, that is, thoseembraced by Formula I and their non-toxic, pharmacologically acceptableacid addition salts, have useful pharmacodynamic properties. Moreparticularly, the compounds of the present invention exhibitbactericidal activities against gram-positive and gram-negativebacteria, as well as fungicidal and trichomonacidal activities, thelatter against Trichomonas vaginalis, for example, in warm-bloodedanimals.

The anti-bacterial activity was determined by the agardiffusion test andby the series-dilution test analogous to the method described by P.Klein in Bakteriologische Grundlagen der ChemotherapeutischenLaboratoriumspraxis, Springer-Verlag, 1957, pages 53-76 and 87-109.

Thus, for example, the following compounds were found to exhibitespecially effective anti-bacterial activities against Staphylococcusaureus SG 511 at concentrations of less than 3 'y/mL, againstStreptococcus aronson at concentrations of less than 2 'y/ml., andagainst Escherichia coli at concentrations of less than 25 'y/mL:

2- '-nitro-2'-furyl) -4-methylamino-thieno 3 ,2-d]

pyrimidine;

2- 5 -nitro-2'-furyl fi-hydroxy-ethyl -amino] -thieno [3 ,2-d]pyrimidine;

2- 5 '-nitro-2'-furyl) -4- B,-y-dihydroxy-n-propyl amino] thieno [3,2-d] pyrimidine;

2-( 5 -nitro-2'-furyl) -4-[ B-hydroxy-n-propyl) amino thieno 3,2-d]pyrimidine;

2- 5'-nitro-2-furyl -4- bis- (fi-hydroxy-ethyl) amino] thieno[ 3,2-dpyrimidine;

2- 5 '-nitro-2'-furyl) -4- [N- fi-hydroxy-ethyl) -methylamino] -thieno[3 ,2-d] pyrimidine;

2-( 5 -nitro-2'-furyl) -4- (fi-methoxy-ethyl) -amino] -6- methyl-thieno[3 ,2-d] pyrimidine;

2- 5 -nitro-2-furyl -4-amino-thieno 3 ,2-d] pyrimidine 2- 5'-nitro-2-furyl -4-acetylamino-thieno [3 ,2-d]

pyrimidine; and

2- 5 '-nitro-2-furyl -4- B -dihydroxy-n-propyl amino] -6-methyl-thieno[3 ,Z-d] pyrimidine.

Likewise, the following compounds were found to be especially effectivetrichomonacides against Tricllomolzas vaginalis at concentrations ofless than 0.1 7/1111.:

2- (5'-nitro-2furyl) -4-[ (/S-hydroxy-n-propyl -amino] thieno [3 ,2-d]pyrimidine;

2- 5-nitro-2-furyl) -4 3 -hydroxy-piperidino) -thieno- [3,2-d]pyrimidine;

2- 5 '-nitro-2-furyl) -4- [N- ,B-hydroxy-ethyl -methylamino] -thieno 3,2-d] pyrimidine;

2- 5 '-nitro-2-furyl -4- 4"-hydroxy-piperidino -thieno- [3 ,Z-d]pyrimidine;

2- (5 -nitro-2'-furyl -4- [4"-hydroxy-nbutyl -amino] thieno [3 ,2-dpyrimidine;

2- 5'-nitro-2-furyl -4-[ ,e-hydroxy-' -diethylamino-npropyl -amino]-thieno [3 ,2-d pyrimidine;

2- 5 -nitro-2'-furyl) -4- dichloroacetyl-amino) -thieno- [3 ,2-d]pyrimidine; and

2- 5 '-nitro'-2'-furyl -4- thiomorpholinol-oxide) thieno [3 ,2-d]pyrimidine.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally ortopically as active ingredients in customary pharmaceuticalcompositions, that is, compositions consisting essentially of an inertpharmaceutical carrier and one effective amount of the activeingredients, such as tablets, coated pills, capsules, wafers, powders,solutions, suspensions, emulsions, syrups, tinctures, lotions,suppositories and the like. One effective oral dosage unit of thecompounds according to the present invention is from 0.166 to 3.34mgm./kg. body weight, preferably 0.83 to 1.67 mgm./ kg. body weight. Theeffective concentration of the compounds in a composition for topicalapplication is from 0.1 to 2.0% by weight, preferably 1% by weight,based on the total weight of the composition.

The following examples illustrate a few pharmaceutical compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of putting the invention intopractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 104 Tablets The tablet composition was compounded from thefollowing ingredients:

Parts 2-(5'-nitro 2' furyl) 4 [(fl-hydroxy-ethyD-amino]-thieno[3,2-d]pyrimidine 100.0 Lactose 63.0 Potato starch 50.0Polyvinylpyrrolidone 5.0 Magnesium stearate v 2.0

Total 220.0

Preparation The thienopyrimidine compound was intimately admixed withthe lactose and the potato starch, the mixture was moistened with anaqueous 10% solution of the polyvinylpyrrolidone, the moist mass wasforced through a 1.5 mm.-mesh screen, the resulting granulate was driedat 45 C. and again passed through the said screen, the dry granulate wasadmixed with the magnesium stearate, and the composition was compressedinto 220 mgm.- tablets in a conventional tablet-making machine. Eachtablet contained mgm. of the thienopyrimidine compound and, whenperorally administered to a warmblooded animal of about 60 kg. bodyweight in need of such treatment, produced very good bactericidaleffects against grampositive and gramnegative bacteria.

EXAMPLE 105 Coated pills The pill core composition was compounded fromthe following ingredients:

Parts 2-(5'-nitro 2' furyl) 4 [(fl-hydroxy-ethyD- amino] -thieno-[ 3,Z-d pyrimidine 50.0 Lactose 30.0 Corn starch 30.0

Parts Gelatin 3.0 Cellulose, microcrystalline 6.0 Magnesium stearate 1.0

Total 120.0

Preparation The thienopyrimidine compound, the lactose and the cornstarch were intimately admixed with each other, the mixture wasmoistened with an aqueous 12% solution of the gelatin, the moist masswas forced through a 1.5 mm.-mesh screen, the resulting granulate wasdried at 45 C. and again passed through a 1.0 mm.-mesh screen, the drygranulate was admixed with the magnesium stearate, and the resultingcomposition was compressed into 120 mgm.-pill cores in a conventionalpill-making machine. The pill cores were then coated with a thin shellconsisting essentially of a mixture of talcum and sugar, and finallypolished with beeswax. Each coated pill contained 50 mgm. of thethienopyrimidine compound and, when administered perorally to awarm-blooded animal of about 60 kg. body weight in need of suchtreatment, produced a very effective bactericidal action againstgrampositive and gramnegative bacteria.

EXAMPLE 106 Vaginal tablets The tablet composition was compounded fromthe following ingredients:

Preparation The thienopyrimidine compound was intimately admixed withthe sorbitol and the carboxymethyl cellulose, the mixture was moistenedwith 150 parts of aqueous 50% ethanol, the moist mass was forced througha 2 mm.-mesh screen, the resulting granulate was dried at 45 C. andagain passed through the said screen, the dry granulate was admixed withthe magnesium stearate, and the composition was compressed into 1000mgm.-tablets in a conventional tablet-making machine. Each tablet contained 100 mgm. of the thienopyrimidine compound and, When administeredby the vaginal route to a female warmblooded animal in need of suchtreatment, produced very effective trichomonacidal effects againstTrichomonas vaginalis.

EXAMPLE 107 Tincture The tincture was compounded from the followingingredients:

Parts 2-( 5 nitro-2-furyl)-4-[(p-hydroxy-ethyn-amino] thieno[3,2-d]pyrimidine 1.0 Polyethyleneglycol 400 99.0

Total 100.0

Preparation The polyethyleneglycol was warmed, the thienopyrimidinecompound was dissolved therein, and the solution was cooled to roomtemperature and filtered. The resulting tincture contained 1% by weightof the thienopyrimidine compound and, when topically applied to a skinarea of a warm-blooded animal infested with grampositive and/orgramnegative bacteria, produced a very eficctive bactericidal action.

30 EXAMPLE 10s The lotion was compounded from the following ingredients:

Preparation The inert ingredients were admixed, the mixture was meltedand heated to 70 C., and the molten mass was emulsified in the distilledwater at the same temperature, the emulsion was cooled to 40 C., and thefinely milled thienopyrimidine compound was uniformly distributedtherein vvith the aid of an immersion homogenizer. The resulting lotioncontained 1% by weight of the thienopyrimidine compound and, whentopically applied to a skin area of a warm-blooded animal infested withgrampositive and/or gramnegative bacteria, produced a very effectivebactericidal action.

EXAMPLE 109 Coated pills with combination of active ingredients The pillcore composition was compounded from the following ingredients:

Parts 2-(5 nitro-2'-furyl)-4-[(B-hydroxy-ethyD-amino]thieno[3,2-d]pyrimidine 50.0 Papaverine 25.0 Corn starch 32.0 Gelatin3.0 Cellulose, microcrystalline 9.0 Magnesium stearate 1.0

Total 120.0

Preparation The thienopyrimidine compound and the papaverine wereintimately admixed with the corn starch, the mixture was moistened withan aqueous 10% solution of the gelatin, the moist mass was forcedthrough a 1.5 mm.- mesh screen, the resulting granulate was dried at 45C. and again passed through a 1.0 mm.-mesh screen, the dry granulate wasadmixed with the cellulose and the magnesiu-m stearate, and thecomposition was compressed into 120 mgm.-pill cores in a conventionalpill-making machine. The pill cores were then coated with a thin shellconsisting essentially of a mixture of talcum and sugar, and finallypolished with beeswax. Each coated pill contained 50 mgm. of thethienopyrimidine compound and 25 mgm. of papaverine and, when perorallyadministered to a warm-blooded animal of about 60 kg. body weight inneed of such treatment, produced very effective smooth muscle relaxingand bactericidal actions.

EXAMPLE 110 Gelatin capsules The capsule filler composition wascompounded from the following ingredients:

Total Preparation The ingredients were intimately admixed with eachother, the mixture was passed through a 1.0 mm.-mesh screen, and 300mgm.-portions thereof were filled into gelatin capsules of suitablesize. Each capsule contained 150 mgm. of the thienopyrimidine compoundand, when perorally administered to a warm-blooded animal of about 60kg. body Weight in need of such treatment, produced a very effectivebactericidal action against gramnegative and grampositive bacteria.

Analogous results were obtained when any one of the otherthienopyrimidines embraced by Formula I or a non-toxic acid additionsalt thereof was substituted for the particular thienopyrimidine inExamples 104 through 110. Likewise, the amount of active ingredient inthese illustrative examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may bemadewithout departing from the spirit of the invention or the scope ofthe appended claims.

We claim:

1. A compound of the formula All wherein R is hydrogen or methyl, and Ris amino, (alkyl of 1 to 5 carbon atoms)-amino,

di-(alkyl of .1 to 4 carbon atoms)-amino, (monohydroxy-alkyl of 2 to 5carbon atms)-amino, (2,3- dihydroxy-n-propyD-amino, (alkoxy of 1 to 2carbon atoms-alkyl of 1 to 3 carbon atoms)-amino, N- (hydroxy-alkyl of 2to 3 carbon atoms)-N-alkyl of 1 to 4 carbon atoms)-amino,N-methyl-D-glucamino, di-(hydroxy-alkyl of 1 to 5 carbon atoms)-amino,[(di-alkyl of 1 to .2 carbon atoms)-amino-alkyl of 2 to 3 carbonatoms]-amino, (1-methyl-2-hydroxyethyl)-amino,(2-phenyl-2-hydroxy-ethyl) amino, (2-hydroxy-3-diethylamino-n-propyl)-amino, (alkanoyl of 1 to 2 carbonatoms)-amino, chloroacetyl-amino, dichloroacetyl-amino, (amino-alkyl of2 to 3 carbon atoms)-amino, (acetyl-amino-alkyl of 2 to 3 carbonatoms)-amino, allylamino, anilino, chloroanilino, methylanilino,hydroxyanilino, methoxyanilino, N- methyl-anilino, benzylamino,phenethyl-amino, cyclohexyl-amino, (hydroxy cyclohexyD-amino, pyr- 32rolidino, piperidino, hydroxy-piperidino, morpholino, thiomorpholino,thiomorpholino-l-oxide, piperazino, N-methyl-piperazino,N-hydroxyethylpiperazino, N- formyl-piperazino orN-carbethoxy-piperazino, or a non-toxic, pharmacologically acceptableacid addition salt thereof.

2. A compound according to claim 1, which is 2-(5'- nitro-2-furyl)-4-methylamino-thieno [3 ,2-d] pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

3. A compound according to claim 1, which is 2-(5'- nitro-2'-furyl -4-[figy-dihydroxy-n-propyl -amino] thieno- [3, 2-d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

4. A compound according to claim 1, which is 2-(5'- nitro-2'-furyl) -4-(fl-hydroxy-ethyl -amino] thieno 3 ,2-d] pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

5. A compound according to claim 1, which is 2-(5'- nitro-2'-furyl)-4-[(B-hydroxy n propyl)-amino]-thieno- [3,2-d]pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

6. A compound according to claim 1, which is 2-('5'- nitro 2' furyl)-4-[bis-(fi-hydroxy-ethyD-amino] -thieno- [3,2-d1pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

7. A compound according to claim 1, which is 2-(5'- nitro-2'-fury l) 4[N-(B-hydroxy-ethyl)methylamino]- thieno[3,2-d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 1, which is 2-(5'- nitro-2-furyl) 4(fi-methoxyethyl amino)-6-methylthieno[3,2-d]pyrimidine or a non-toxic,pharmacologically acceptable acid addition salt thereof.

9. A compound according to claim 1, which is 2-(S-nitro-2-fury1)-4-amino-thieno[3,2-d] pyrimidine or a nontoxic,pharmacologically acceptable acid addition salt thereof.

10. A compound according to claim 1, which is4-acetylamino-2-(5-nitro-2'-furyl)-thieno[3,2-d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

11. A compound according to claim 1, which is 4-(fi,'ydihydroxy npropyl-amino)-6-methyl-2-(5-nitro-2-furyl)-thieno[3,2-d]pyrimidine or anon-toxic, pharmacologically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 9/ 1966 Ohnacker et a1. 260-42565R 5/ 1967 Ohnacker et al. 260-256.6 R

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner 552 3U1 ITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,661,908 Dated y 9, 97

EBERHARD WOITUN and WOLFGANG REU'I'ER Inventor(s) It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

T7501. 5, line 42 correct "12.50" to read --12.59--. v

Col. 6, line 2 correct "12.85" to read ---l2.8 l--.

Col. 8, lines 3,4,5 delete M.P'. 148-150C. from t2- (2'-furl)-4-[fi3,4fdihydroxy--n-prop; rl)--amino]- th eno[3,2-d]pyridine" line 10insert heading --2-(2-'-Furyl)- l-acetylaminothieno[3,2-d ]pyrimidin001.10, line 26 correct the spelling of "thieno".

-CH2-CH2-OCH3 Col. 12, line 20 correct "3,3-d" to read --3,2-d--;

line 33 correct "16" to read --l66--.

9 Col. 22, line 19 correct "HN-CH -CH -H-C-CH N to read: 0

Col. 26,

line 35 correct "thiono" to read --thieno--.

Signed and sealed this 27th day of March 1973 (SEAL) Attest:

EDWARD M. FLETCHER,JR. ROBERT GOTTSCHALK Attest ng Officer Commissionerof Patents

